Influence of albumin infusion on the urinary excretion of beta2-microglobulin in patients with proteinuria

Most filtered proteins are reabsorbed by the renal proximal tubule by a mechanism that involves binding to the brush border membrane and endocytosis. Under normal conditions the low-molecular-weight protein beta2-microglobulin (beta2M), which is used to detect tubular injury, is reabsorbed almost completely. However, in proteinuric patients an increased urinary excretion of beta2M may not simply reflect tubular damage but might also result from a decreased tubular reabsorption due to competitive mechanisms. To examine the magnitude of such an effect we have studied the renal effects of albumin infusion (40 g in 2 h of a 20% solution) in 10 patients with a glomerular disease and proteinuria >3.5 g/24 h. Before, during and after albumin infusion the GFR (inulin clearance), RPF (PAH clearance), blood pressure and the urinary excretion of albumin, IgG, transferrin and beta2M were measured. Albumin infusion resulted in a slight decrease of the GFR (72 +/- 11 ml/min before and 67 +/- 10 ml/min after infusion), an increase of the RPF (379 +/- 66 ml/min before and 445 +/- 83 ml/min after), a decrease of the filtration fraction (0.20 before and 0.17 after), and hemodilution. After infusion the urinary excretion of albumin increased from 4.5 +/- 0.7 to 8.4 +/- 1.6 mg/min (p < 0.05). The urinary excretion of IgG and transferrin increased, probably reflecting a change in glomerular size-selectivity. In contrast, the urinary excretion of beta2M did not change significantly (baseline 12 +/- 5 microg/min, end 13 +/- 6 microg/min, percentage change 16.8 +/- 11%). To correct for changes in tubular load we calculated the fractional reabsorption of beta2M. The initial rise in albuminuria during infusion did not affect fractional tubular reabsorption (Delta%: 0. 72 +/- 0.52%, median 0.005%). In the period after infusion a slight decrease was noted (median -0.33%, p < 0.01). A decrease in the fractional reabsorption was particularly observed in patients with pre-existing tubular damage. In conclusion: infusion of albumin in proteinuric patients has no clinically relevant effect on the tubular reabsorption of beta2M. Therefore, beta2M is useful as a parameter to detect tubular injury and alterations in tubular handling of proteins in patients with proteinuria and glomerular diseases.     

Effect of angiotensin II on proximal tubular reabsorption in normal humans.

The effects of angiotensin II (AII) on proximal tubular reabsorption have been evaluated in 6 healthy volunteers under normal salt and water balance. One-hour clearance periods were performed before, during and after the infusion of pressor doses of AII; in 3 of the 6 subjects, the study was repeated with lower doses of AII. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were determined by the clearances of inulin and PAH, and the fractional excretion of lithium (FELi) was considered as an index of proximal sodium reabsorption. The effects of AII on the fractional excretion of beta 2 microglobulin (FE beta 2M) were also studied. Both doses of AII decreased GFR and RPF and increased the filtration fraction (FF); the modifications of these parameters, as well as the reduction of FELi and the fractional excretion of sodium (FENa) and the increase of plasma aldosterone and of plasma atrial natriuretic peptide (ANP), were more evident with pressor doses of AII, which increased the blood pressure from 129/83 to 142/95 mm Hg (p less than 0.01). AII did not modify FE beta 2M in either study. During AII, FELi decreased less than FENa and both were closely and inversely related to the variations of FF, whilst no relationship was present between FE beta 2M and FF. These results suggest that, in normal humans, the AII-induced rise of FF may be an important factor, even if not the only one, in enhancing the proximal reabsorption of lithium and thus of sodium, whilst it does not affect the absorption of beta 2M.     

Renal albumin absorption in physiology and pathology

Albumin is the most abundant plasmaprotein serving multiple functions as a carrier of metabolites, hormones, vitamins, and drugs, as an acid/base buffer, as antioxidant and by supporting the oncotic pressure and volume of the blood. The presence of albumin in urine is considered to be the result of the balance between glomerular filtration and tubular reabsorption. Albuminuria has been accepted as an independent risk factor and a marker for renal as well as cardiovascular disease, and during the past decade, evidence has suggested that albumin itself may cause progression of renal disease. Thus, the reduction of proteinuria and, in particular, albuminuria has become a target in itself to prevent deterioration of renal function. Studies have shown albumin and its ligands to induce expression of inflammatory and fibrogenic mediators, and it has been hypothesized that increased filtration of albumin causes excessive tubular reabsorption, resulting in inflammation and fibrosis, resulting in the loss of renal function. In addition, it is known that tubular dysfunction in itself may cause albuminuria owing to decreased reabsorption of filtered albumin, and, recently, it has been suggested that significant amounts of albumin fragments are excreted in the urine as a result of tubular degradation. Thus, although both tubular and glomerular dysfunction influences renal handling of albumin, it appears that tubular reabsorption plays a central role in mediating the effects of albumin on renal function. The present paper will review the mechanisms for tubular albumin uptake and the possible implications for the development of renal disease.     

Renal sodium and water handling in hypothyroid patients: the role of renal insufficiency

The mechanism responsible for renal tubular abnormalities in sodium and water excretion in hypothyroid patients is poorly understood. To evaluate the possible contribution of the reduced glomerular filtration rate of hypothyroidism to these abnormalities, tubular function in hypothyroid patients was compared with that in patients with chronic renal failure and in normal subjects. The lithium clearance method and oral water loading were used to evaluate parameters of tubular sodium and water handling, respectively. The hypothyroid and the chronic renal failure patients were selected to have similar reductions in glomerular filtration rate. As compared to the normal subjects, the hypothyroid and chronic renal failure patients had a decrease in proximal sodium reabsorption and an increase in distal sodium reabsorption. The changes in tubular handling of sodium were not different in the hypothyroid and the chronic renal failure patients. Maximal urinary flow rate and free water clearances were similarly reduced in the hypothyroid patients and the chronic renal failure patients. For all subjects studied, proximal sodium reabsorption and maximal urinary volume were directly correlated with the glomerular filtration rate, and distal nephron sodium reabsorption was proportionate to delivery of sodium from the proximal tubule. The results suggest that the abnormalities in tubular sodium and water handling in hypothyroid patients are comparable to those present in other patients with a similar degree of renal insufficiency. Thus, the tubular abnormalities in hypothyroidism may be a consequence of the associated decrease in glomerular filtration rate.     

Mechanism of osmotic diuresis

Mannitol might inhibit paracellular reabsorption of water and sodium chloride in the proximal tubules by reducing the osmotic driving force. We examined this hypothesis in anesthetized dogs. Bicarbonate reabsorption was kept constant by sodium bicarbonate infusion, and transcellular sodium chloride reabsorption was inhibited by ethacrynic acid. The glomerular filtration rate (GFR) was varied by altering renal perfusion pressure. Mannitol infusion reduced sodium chloride reabsorption from 62 +/- 5% to 33 +/- 5% of the filtered load. The calculated increase in reabsorbate osmolality, averaging 82 +/- 6 mOsm/kg H2O, was due to sodium bicarbonate and equalled the increase in plasma osmolality. Mannitol concentration averaged 81 +/- 7 mM in plasma and 101 +/- 12 mM in urine. A linear relationship between reabsorption and GFR (glomerulo-tubular balance) was maintained over the same range of GFR before and after mannitol infusion. Mannitol infusion reduced sodium chloride reabsorption from 2.6 to 1.4 moles for each mole of sodium bicarbonate reabsorbed. During mannitol infusion, acetazolamide inhibited sodium bicarbonate reabsorption as in control experiments, but reduced sodium chloride reabsorption less. We conclude that reduced water reabsorption increases sodium bicarbonate concentration in the paracellular fluid as much as mannitol concentration is raised in the plasma and glomerular filtrate. Along the proximal tubules, net osmotic force is progressively reduced as mannitol concentration rises, accounting for reduced water and sodium chloride reabsorption.     

Nitric oxide and superoxide in the renal medulla: a delicate balancing act

PURPOSE OF REVIEW: Endothelial nitric oxide synthase (eNOS) and nicotinamide adenine dinucleotide (phosphate) oxidase [NAD(P)H oxidase] are both expressed in tubular epithelial cells within the renal medulla, particularly the thick ascending limb of the loop of Henle (mTALH). Thick ascending limbs contribute to long-term blood pressure control, both because they reabsorb approximately 30% of filtered sodium, and because they produce paracrine factors like nitric oxide (NO) that control medullary blood flow (MBF), which in turn has a major impact on tubular sodium reabsorption. Herein, we review recent evidence for roles of NO and superoxide (O2*-) in autocrine control of tubular sodium reabsorption, and in paracrine control of MBF. RECENT FINDINGS: O2*- can have a direct action to reduce MBF, and to enhance sodium reabsorption from mTALH. These actions oppose those of NO produced in mTALH, which inhibits tubular sodium reabsorption (autocrine) and increases MBF (paracrine). NO and O2*- also oppose each other's actions through chemical combination to produce peroxynitrite. Thus, interactions between NO and O2*-, at both the chemical and cellular levels, likely contribute to long-term blood pressure control. This hypothesis is supported by recent data showing that sodium retention and hypertension can develop when the balance of production of these free radicals is tipped towards O2*-, such as in diabetes, atherosclerosis and renin-angiotensin-system activation. SUMMARY: Interactions between O2*- and NO produced within the mTALH regulate tubular and vascular function in the renal medulla. Dysregulation of these systems in states of oxidative stress likely promotes salt and water retention, and thus hypertension.     

Renal function in cyanotic congenital heart disease

We performed renal function tests in 18 young patients, 1.8-14.6 years of age, with cyanotic congenital heart disease (CCHD). Glomerular filtration rate was normal (116 +/- 4.5 ml/min/1.73 m2), and renal plasma flow was decreased (410 +/- 25 ml/min/1.73 m2) with a rise in the filtration fraction (29 +/- 1.1%). The suggested pathophysiologic explanation of these findings is that the blood hyperviscosity seen in patients with CCHD causes an overall increase in renal vascular resistance with a rise in intraglomerular blood pressure. Despite a sluggish flow of blood in the glomerular capillary bed, the effective filtration pressure was adjusted to conserve the glomerular filtration rate. In addition to these renal hemodynamic parameters, we also studied renal acidification and tubular sodium and water handling during a forced water diuresis. Our data indicate that children with CCHD have a mild to moderate normal ion gap metabolic acidosis due to a low proximal tubular threshold for bicarbonate. Proximal tubular sodium and water reabsorption under these conditions were somewhat increased, though not significantly, probably due to intrarenal hydrostatic forces, in particular the rise in the oncotic pressure in the postglomerular capillaries in patients with high hematocrit values. The distal tubular functions such as sodium handling and acidification were not affected.     

Use of beta 2 microglobulin to diagnose tubulo-interstitial renal lesions in children

Fractional excretion (FE) of beta 2 microglobulin (beta 2M) was studied in children with glomerular (N = 114), tubular (N = 50) or other (N = 18) renal diseases. FE-beta 2M (normal less than 0.36%) was significantly (P less than 0.001) lower in glomerular diseases (mean 0.104%) than in tubular lesions (mean 4.27%). Unexpectedly, several patients with glomerular disease were found to have increased values for FE-beta 2M. To determine whether this was due to a tubular component in a primary glomerular disease process, FE-beta 2M was measured in 30 children with various glomerulopathies who underwent renal biopsy. Thirteen of these patients had tubulo-interstitial lesions in addition to their glomerular disease. FE-beta 2M in these patients averaged 3.76% (range 0.14 to 44.6%); only two results were normal. Mean FE-beta 2M in the 17 patients without biopsy evidence of tubulo-interstitial disease was 0.063% (range 0.02 to 0.34%); all values were in the normal range. The types of glomerular diseases in the two groups of patients were similar. Patients with a glomerular lesion complicated by tubulo-interstitial lesions had a poorer prognosis than did those with a pure glomerular disease. The high incidence of tubulo-interstitial lesions in patients with glomerular diseases was unexpected. Our data demonstrates that FE-beta 2M represents a reliable non-invasive method to diagnose such involvement. Measurements of beta 2M also provide a convenient method to follow the course and response to treatment of renal tubular injury.     

Intrarenal blood oxygenation and renal function measured by magnetic resonance imaging during long-term cyclosporine treatment

Treatment with cyclosporine (CsA) markedly affects the renin-angiotensin-aldosterone system in parallel with an increase in the net tubular reabsorption or a decrease in secretion. Since tubular reabsorption is closely linked to medullary oxygen consumption, the aim of the present study was to investigate the intrarenal oxygenation and renal function in response to CsA. Six mini G?ttingen pigs were treated with CsA (10 mg/kg/d) for 6 months. The intrarenal oxygenation was indirectly measured as R2* obtained with a multiecho gradient-echo magnetic resonance imaging (MRI) sequence. Single-kidney renal blood flow (skRBF) was measured by a velocity-sensitive gradient-echo MRI sequence. Relative single-kidney glomerular filtration rate (rskGFR) was derived from the MRI time-activity curve in response to an intravenous bolus of Gd-DTPA (0.05 mmol/kg). The present study showed that administration of CsA increased the medullary R2* (23.1 Hz vs 19.0 Hz, P = .002), whereas R2* was slightly increased in the renal cortex (13.3 Hz vs 12.3 Hz, P = .012). In parallel, rskGFR increased significantly (47.2 mL/min vs 19.8 mL/min, P = .005) but skRBF was unchanged (197.6 mL/min vs 202.5 mL/min, P > .05). The increased R2* in the renal medulla indicated that CsA augments the tubular reabsorption of water, leading to increased oxygen consumption. The supply of oxygen to the kidney was, however, maintained during treatment with CsA as suggested by an unchanged renal blood flow. The increased tubular reabsorption was compensated for by an elevated glomerular filtration rate.     

Oxygen free radical mediated renal dysfunction

Postischemic renal dysfunction (PIRD) is characterized by a reduction in glomerular filtration and tubular reabsorption of solute. The relative contribution of oxygen free radicals (OFRs) generated during reperfusion remains unclear. This study characterized the renal response to OFRs--independent of an ischemic insult. Isolated rat kidneys were perfused at 37 degrees C and 90-100 mm Hg with a modified Krebs' buffer. Hypoxanthine (25 mumole) and xanthine oxidase (1 unit) were combined and infused proximal to the kidney. There was a 50% increase in vascular resistance. This was accompanied by a 30% reduction in perfusate flow rate and a 70% reduction in glomerular filtration rate. There was also a significant reduction in urine flow rate and oxygen consumption. The percentage reabsorption of filtered water and sodium by the renal tubules was not diminished, however. This pattern was not observed when the xanthine oxidase was inactivated or when the perfusate was pretreated with superoxide dismutase (250 units/ml) and catalase (500 units/ml). The generation of OFRs, independent of an ischemic insult, causes a decrease in glomerular filtration out of proportion to the decrease in renal flow similar to that observed with PIRD. OFRs may contribute to the hemodynamic and glomerular alterations seen with PIRD. Factors other than OFRs, probably associated with ischemia, must be responsible for the tubular dysfunction.     

Renal water and sodium handling during gradated unilateral ureter obstruction

OBJECTIVE: Unilateral complete obstruction of the ureter (UUO) is associated with characteristic changes in renal function. To improve the understanding of how urine concentration directly is affected by changes in pelvic pressure, changes in renal salt and water handling along the nephron and collecting duct were examined. MATERIAL AND METHODS: Pelvic pressure was raised stepwise using an adjustable lever inserted in the right ureter. Urine samples were collected from the tip of the catheter by way of an overflow system. Water and sodium handling in the distal and proximal tubules were measured by the lithium clearance technique. Renal blood flow (RBF) was measured with implanted ultrasonic flow probes. Catheters were placed in both renal veins and glomerular filtration rate (GFR) and filtration fraction were calculated using renal extraction of (51)Cr-EDTA independent of urine sampling. RESULTS: The sequence of changes for each parameter is provided. The parameters did not show a uniform pattern from which specific threshold values could be derived. However, the mean value of the following parameters were markedly changed at specific pressures: (1) at 10 cm H(2)O ipsilateral urine output decreased rapidly and distal absolute reabsorption of sodium (DAR(H2O)) decreased, (2) at 20 cm H(2)O GFR started to decline rapidly, (3) at 30 cm H(2)O urine output was impaired, and (4) at 40 cm H(2)O proximal absolute reabsorption of water (PAR(H2O)) showed a decreasing tendency in all pigs together with impairment in tubular sodium handling. Furthermore, free water clearance was slightly impaired (-0.26 +/- 0.15 at baseline and -0.15 +/- 0.08 ml/min at maximum pressure) and ipsilateral RBF decreased from 171.1 +/- 12.4 ml/min at baseline to 136.3 +/- 12.3 ml/min at ureteral pressure of 80 cm H(2)O (p < 0.05). Consistent with that, ipsilateral renal vascular resistance increased with increasing pressure in the renal pelvis. CONCLUSION: Water reabsorption and sodium handling is progressively impaired with increasing pelvic pressure. GFR and RBF are reduced in parallel. The study shows that the kidney responds to ureteral obstruction is unique and individual.     

Abnormal circadian rhythm of diuresis or nocturnal polyuria in a subgroup of children with enuresis and hypercalciuria is related to increased sodium retention during daytime

PURPOSE: In a subgroup of children with enuresis an increase in nighttime water and solute excretion has been documented. To investigate if modifications in renal function are involved in nocturnal enuresis, we assessed circadian variation in natriuresis and tubular sodium handling in polyuric hypercalciuric children. MATERIALS AND METHODS: A total of 10 children with proved hypercalciuria and nocturnal polyuria and 10 age matched controls were included in the study. A 24-hour urine collection was performed in 8 sampling periods for measurement of urinary sodium excretion. Segmental tubular sodium transport was investigated during a daytime oral water load test and calculated according to standardized clearance methodology. RESULTS: The children with enuresis showed a marked increase in the fractional excretion of sodium during the night (0.93% +/- 0.36%), while daytime sodium excretion was decreased (0.84% +/- 0.23%). Analysis of segmental tubular sodium transport revealed decreased delivery of sodium to distal tubule (C(H2O) + C(Na) = 10.7 ml/100 ml glomerular filtration rate), indicating increased proximal tubular sodium reabsorption but also stimulation of distal sodium reabsorption as demonstrated by increased fractional distal sodium reabsorption (92.9% +/- 2.2%, controls 90.5% +/- 2.9%). Increased distal reabsorption was associated with increased fractional potassium excretion (17.5% +/- 2.7%, controls 13.6% +/- 6.4%), indicating increased distal tubular sodium/potassium exchange. CONCLUSIONS: No intrinsic defect in renal tubular sodium transport was found, but during the day increased sodium reabsorption in proximal and distal tubules was observed, suggesting extrarenal factors to be involved in altered circadian variation in solute and water excretion by the kidney.     

Cyclosporine inhibits renal uric acid transport in renal transplants not in children treated for nephrotic syndrome

Children with various grades of renal insufficiency (CON group) maintained uric acid excretion over a range of glomerular filtration rate (GFR) from 27 to 160 ml/min*1.73m2 despite a decreased filtered load which was paralleled by glomerular filtration of uric acid. This was achieved by a compensatory decrease of net uric acid reabsorption (TUA) and an increasing fractional excretion of uric acid (FEUA) with decreasing GFR. Although there was a decreased GFR in the group of children after transplantation (NTx group) there was no difference in TUA and FEUA between the NTx group and the CON group. Uric acid transport was not affected in children treated with Cyclosporine (CyA) for nephrotic syndrome (NEPH group) compared to the CON group. Decreased fractional phosphate reabsorption in the NTx group suggests proximal tubule damage associated with disturbed uric acid handling. Under conditions of water diuresis hyperuricemia seen in NTx may result from an indirect effect of renal ischemic damage due to the transplantation procedure causing disturbance of proximal tubular uric acid (active) secretion/reabsorption.     

The effect of acute and chronic protein loading on urinary pepsinogen A excretion

In 8 healthy male volunteers, urinary excretion (UE) and fractional clearance (FC) of pepsinogen A (PGA), beta 2-microglobulin (beta 2-m) and albumin were measured after 6 days high protein diet (HPD; 2.0 g/kg/day) and compared to values obtained after 6 days low protein diet (LPD; 0.5 g/kg/day). In addition, the effect of an acute protein load (APL; 500 g beef) on these variables were measured. Both chronic and acute protein loading induced a rise in glomerular filtration rate (GFR) of about 10% together with a parallel rise in effective renal plasma flow. UE PGA and FC PGA increased both after HPD (UE PGA 1,707 +/- 1,106 ng/min; FC PGA 23 +/- 12%) as compared to LPD (UE PGA 1,200 +/- 987 ng/min, p less than 0.01; FC PGA 18 +/- 12%, p less than 0.05), and after APL (UE PGA 2,276 +/- 1,389 ng/min; FC PGA 26 +/- 16%) as compared to baseline (UE PGA 1,418 +/- 965 ng/min, p less than 0.02; FC PGA 21 +/- 12%, p less than 0.05). UE and FC of beta 2-m and albumin were not affected by protein loading. As PGA is nearly freely filtered, it is concluded that the increase in fractional PGA clearance reflects a decrease in fractional tubular PGA reabsorption. Our results suggest that an increase in fractional protein clearance after protein loading is not necessarily due to an impaired glomerular permselectivity but represents a decreased fractional tubular reabsorption as a result of a GFR-mediated increase in filtered load without a concomitant increase in tubular reabsorption.     

Dopamine increases renal oxygenation: a clinical study in post‐cardiac surgery patients

Background: Imbalance of the renal medullary oxygen supply/demand relationship can cause ischaemic acute renal failure (ARF). The use of dopamine for prevention/treatment of ischaemic ARF has been questioned. It has been suggested that dopamine may increase renal oxygen consumption (RVO₂) due to increased solute delivery to tubular cells, which may jeopardise renal oxygenation. Information on the effects of dopamine on renal perfusion, filtration and oxygenation in man is, however, lacking. We evaluated the effects of dopamine on renal blood flow (RBF), glomerular filtration rate (GFR), RVO₂ and renal O₂ demand/supply relationship, i.e. renal oxygen extraction (RO₂Ex). Methods: Twelve uncomplicated, mechanically ventilated and sedated post‐cardiac surgery patients with pre‐operatively normal renal function were studied. Dopamine was sequentially infused at 2 and 4 ug/kg/min. Systemic haemodynamics were evaluated by a pulmonary artery catheter. Absolute RBF was measured using two independent techniques: by the renal vein thermodilution technique and by infusion clearance of paraaminohippuric acid (PAH), with a correction for renal extraction of PAH. The filtration fraction (FF) was measured by the renal extraction of ⁵¹Cr‐EDTA. Results: Neither GFR, tubular sodium reabsorption nor RVO₂ was affected by dopamine, which increased RBF (45–55%) with both methods, decreased renal vascular resistance (30–35%), FF (21–26%) and RO₂Ex (28–34%). The RBF/CI ratio increased with dopamine. Dopamine decreased renal PAH extraction, suggestive of a flow distribution to the medulla. Conclusions: In post‐cardiac surgery patients, dopamine increases the renal oxygenation by a pronounced renal pre‐and post‐glomerular vasodilation with no increases in GFR, tubular sodium reabsorption or renal oxygen consumption.     

The effect of saline-induced extracellular volume expansion on the kidney function

The functional parameters of renal function of non-hydrated and hydrated dogs (saline-infused to an extent of 1–2% of the body weight) have been compared.The directly measured renal blood flow and the total renal vascular resistance were the same in the two groups. No difference has been found in glomerular filtration rate, theC _inulin was the same in the two groups. There was no important difference in the PAH clearance and PAH extraction. In the hypervolaemic group, the sodium and water excretion was about threefold that of the non-hydrated animals. The plasma protein concentration was significantly lower in the hydrated group.In our experiments we did not find glomerular factors responsible for the increase of sodium and water excretion. The decrease of tubular reabsorption is attributed partly to the decreased plasma protein concentration, partly to unknown (perhaps natriuretic) humoral factors.     

Complete absence of tubular glucose reabsorption: a new type of renal glucosuria (type 0)

Primary renal glucosuria is an inherited defect of tubular glucose reabsorption and usually classified in type A and type B. We now observed a new type in a 15-year-old boy who had a complete absence of tubular glucose reabsorption. His father had a daily glucosuria of 1.1 g/1.73 m2 and his mother of 2.7 g/1.73 m2. Two siblings excreted 0.4 g/1.73 m2 and 0.3 g/1.73 m2 glucose and one sister had no glucosuria. The proband excreted daily 136 to 160 g/1.73 m2 glucose accompanied by normal blood glucose levels between 75-105 mg/dl. The glomerular filtration rate (inulin clearance) was 148-153 ml/min/1.73 m2 and the endogenous glucose clearance was 112-160 ml/min/1.73 m2 when blood glucose levels were 72-82 mg/dl. Thus, glucose clearance was nearly identical to inulin-clearance. After intravenous glucose loading with a blood glucose concentration of 261-342 mg/dl, glucose clearance remained in the same range and tubular glucose reabsorption was virtually absent. There were no disturbances in tubular reabsorption of other substrates. This new type of primary renal glucosuria was not recognized thus far, and we propose to call it type O glucosuria. The family tree revealed consanguinity and most probably the proband is homozygous and both his parents are heterozygous for type O renal glucosuria.     

Cyclosporine Inhibits Renal Uric Acid Transport in Renal Transplants not in Children Treated for Nephrotic Syndrome

Children with various grades of renal insufficiency (CON group) maintained uric acid excretion over a range of glomerular filtration rate (GFR) from 27 to 160 ml/min*l. 73m² despite a decreased filtered load which was paralleled by glomerular filtration of uric acid. This was achieved by a compensatory decrease of net uric acid reabsorption (Tua) and an increasing fractional excretion of uric acid (FEua) with decreasing GFR. Although there was a decreased GFR in the group of children after transplantation (NTx group) there was no difference in Tua and FEua between the NTx group and the CON group. Uric acid transport was not affected in children treated with Cyclosporine (CyA)for nephrotic syndrome (NEPH group) compared to the CON group. Decreased fractional phosphate reabsorption in the NTx group suggests proximal tubule damage associatedwith disturbed uric acid handling. Under conditions of water diuresis hyperuricemia seen in NTx may result from an indirect effect of renal ischemic damage due to the transplantation procedure causing disturbance of proximal tubular uric acid (active) secretionlreabsorption.     

The renal uptake of proteins: a nonselective process in conscious rats

The selectivity of the renal reabsorption of proteins has been investigated by competition experiments in conscious rats. The animals were intravenously injected with increasing doses of proteins over a wide range of net charge and size, including lysozyme, cytochrome C, metallothionein, beta 2-microglobulin, retinol-binding protein, albumin and IgG. The urinary excretion of exogenous proteins injected concomitantly (human beta 2-microglobulin, retinol-binding protein, albumin and/or egg white lysozyme depending on the experiment) and of rat beta 2-microglobulin, albumin and IgG was determined with specific immunoassays. The results show that low molecular weight cationic proteins and low or high molecular weight anionic proteins can increase each other's urinary excretion. Several observations strongly suggest that these effects result from a competitive inhibition of renal uptake. The phenomenon is dose-related in most cases and, as evidenced by cytochrome C injection, transient, reproducible and saturable. In addition, the injected proteins induce a tubular type proteinuria irrespective of their net charge and size. In the case of cationic proteins, this finding excludes the possibility of an enhanced glomerular permeability due to a partial neutralization of the glomerular polyanion which, as demonstrated with protamine sulfate, entails a glomerular type proteinuria. These quantitative data on the mutual inhibition of renal uptake of a wide spectrum of specific proteins lead us to challenge the concept of charge- and size-selective tubular reabsorption of proteins, and to postulate that proteins filtered through the glomeruli are taken up by common tubular endocytotic sites irrespectively of their physicochemical features. As demonstrated by the ability of beta 2-microglobulin and IgG to inhibit the uptake of lysozyme, the affinity of a protein for reabsorption sites is not simply related to its size and net positive charge. Evidence is also presented that proteins, when administered intravenously at high doses, induce a lysosomal enzymuria most likely reflecting a stimulated exocytosis.     

Compensatory responses to nephron deficiency: Adaptive or maladaptive?

Compensatory renal growth is a characteristic adaptation to reduced renal mass that appears to recapitulate the normal pattern of maturation of the kidney during the postnatal period. Hypertrophy of tubules (predominantly the proximal tubule) and glomeruli is accompanied by increased single nephron glomerular filtration rate and tubular reabsorption of sodium. We propose that the very factors, which contribute to the increase in growth and function of the renal tubular system, are, in the long term, the precursors to the development of hypertension in those with a nephron deficit. The increase in single nephron glomerular filtration rate is dependent on multiple factors, including reduced renal vascular resistance associated with an increased influence of nitric oxide, and a rightward shift in the tubuloglomerular feedback curve, both of which contribute to the normal maturation of renal function. The increased influence of nitric oxide appears to contribute to the reduction in tubuloglomerular feedback sensitivity and facilitate the initial increase in glomerular filtration rate. The increased single‐nephron filtered load associated with nephron deficiency may promote hypertrophy of the proximal tubule and so increased reabsorption of sodium, and thus a rightward shift in the pressure natriuresis relationship. Normalization of sodium balance can then only occur at the expense of chronically increased arterial pressure. Therefore, alterations/adaptations in tubules and glomeruli in response to nephron deficiency may increase the risk of hypertension and renal disease in the long‐term.